Cystic fibrosis (CF) is an autosomal recessive disorder that affects approximately 30,000 individuals in the United States. The primary defect results from mutations of the cystic fibrosis transmembrane conductance regulator gene, which codes for the CFTR chloride channel. The protein is expressed predominantly on the apical surface of epithelial cells throughout the body (although low level expression has been detected in other tissues). Over 2,000 disease causing mutations have been identified in the CFTR gene, with the majority of patients (−90%) exhibiting at least one allele with the F508del mutation. Disease causing mutations fall into 5 classifications that result in abnormal CFTR protein that is either truncated, misprocessed/mislocalized, lacking channel gating function, or malformed due to improper gene splicing. With advances in new-born and other screenings, CF is usually diagnosed at birth. Although the determinants of disease are well characterized, forecasting disease progression has been extremely difficult and as of yet unsuccessful.
Care for CF patients has advanced rapidly over the past two decades, with an increase in patient longevity and quality of life that is unprecedented. The reasons for these improvements include a number of factors. First, a robust CFF Patient Registry (CFF-PR) has collected patient data from nearly all CF patients in the US, allowing assessment of outcomes and treatment responses. Next, there have been dramatic advances in new CF therapeutics (e.g. the development of recombinant human DNase, inhaled antibiotics including dissolved and dry powder tobramycin, aztreonam, hypertonic saline, low dose azithromycin to control inflammation, FDA approval of standardized pancreatic enzyme replacement, and most recently genotype-specific CFTR modulators such as KALYDECO® (4) and ORKAMBI® (5). In tandem with these new treatments, there has been a focus on the development of CF care guidelines and standardization of care across accredited CF care centers. This has helped to ‘raise all boats’ in the CF care community, accompanied by center-specific data to drive local quality improvement. Finally, understanding of disease severity predictors has advanced significantly, including the importance of weight in predicting pulmonary stability, the contribution of chronic Pseudomonas and MRSA infection to pulmonary decline and mortality, and the relationship between poorly controlled diabetes and disease progression. Indeed, these advancements have increased the median survival of CF patients to 41 years (CFF-PR—2014), and nearly 50% of CF patients alive today are adults.
Accompanying the improvements in CF outcomes are a number of challenges that urgently require attention. There have been dramatic global improvements in the CF disease trajectory, but many patients have not fully benefited from the advancements described above. (FIG. 3.) Indeed, the average age of death of CF patients in a given year has remained remarkably static, with most patients dying of CF lung disease during their third decade of life (CFF-PR 2014 statistics). The burden of care also remains a significant challenge, as most adolescents and young adults need to spend approximately two hours daily dedicated to therapies that maintain health. Adherence to complex care regimens is often untenable, and this has led to the need to ‘personalize’ care such that patients commit to daily therapies that are most likely to benefit them individually. These commitments increase during periods of instability, and treatment of PE remains highly interruptive to daily care and negatively impacts quality of life. They also are sentinel markers of disease progression, as 25% of CF patients fail to recover lung functions following PEs. The benefits of care improvements have also challenged our capacity to monitor CF lung disease and CF manifestations in other organs. Assessing the relative benefit of new therapies in the context of relatively normal lung function (as measured by routine spirometry) is particularly challenging for CF providers. This requires the development of more sensitive tools to identify subjects most likely to benefit from various interventions and to monitor the impact of new therapies added to care plans. Finally, the conduct of clinical trials to advance CF outcomes and interventions can no longer rely on standard outcome measures such as FEVi, as excessively large and/or long clinical trials are needed to demonstrate improvements in crude measurements such as lung function. Thus, the CF field stands at a crossroads, where the benefits of the past limit the capacity to advance therapies and personalize care when relying upon standard measures of disease status.
The natural history of the disease is well studied; but disease progression is not well understood. Pulmonary decline typically begins in adolescence, but current measures tend to follow rather than predict outcomes. For example, if a marker predicted disease instability and erratic swings in lung function, established or novel interventions to prevent decline could be implemented. Several clinical measures track disease progression, including forced expiratory volume in 1 sec (FEV1), body mass index (BMI) and pulmonary exacerbations (PE). Presently, intervention is driven by lagging indications of lung function decline, which is far less beneficial than intervening in at risk subpopulations before decline is manifest. Therefore, markers that predict CF disease progression are highly desirable, as they would preemptively identify those at risk of future disease progression, allowing caregivers to tailor treatments and select intervention to prevent pulmonary decline. Personalizing therapy is a critical need in CF, as broad application of all available therapies leads to a high daily treatment burden and poor adherence. These measures are lagging indicators of disease progression that result from molecular changes directly or indirectly related to CFTR dysfunction. Furthermore, current monitoring of lung function data is inadequate, and fails to utilize novel biostatistical tools to identify patients at risk for future decline.
CF care has significantly increased the life span of patients, but the disease remains highly morbid and fatal. Aggressive therapy has been shown to enhance quality of life and improve survival (20); however, it is impractical and expensive to aggressively treat all patients proactively without evidence of disease progression. Therefore, caregivers have depended on outcomes measures, most of which are lagging indicators, to guide treatment decisions. Novel outcome measures of lung function decline that are superior to presently used measures are needed for improving CF patient health and survival, and personalizing care. The disclosed methods address one or more of aforementioned needs in the art.